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Review Article

Genetic Association of Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Chen, Li Jia PhD FCOphthHK∗,†

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Asia-Pacific Journal of Ophthalmology: March-April 2020 - Volume 9 - Issue 2 - p 104-109
doi: 10.1097/01.APO.0000656976.47696.7d
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Age-related macular degeneration (AMD) is a degenerative disease of the macula among elderly individuals. It is a leading cause of irreversible central vision loss among people aged 50 years or older in the developed world.1 AMD can be staged into early, intermediate, and advanced AMD. The latter can be further classified into 2 forms: geographic atrophy (GA) that involves the macula, and neovascular age-related macular degeneration (nAMD).1 The nAMD, which is featured by choroidal neovascularization (CNV), accounts for the majority of cases with severe visual loss due to AMD. Polypoidal choroidal vasculopathy (PCV), which is usually considered as a subtype of nAMD, is an exudative maculopathy characterized by abnormal polypoidal dilatations arising from terminal ends of a branching vascular network located beneath the retinal pigment epithelium.2,3 The polypoidal lesions in PCV are currently best visualized on indocyanine green angiography (ICGA), whereas the lesions in CNV can typically be detected by fundus fluorescein angiography. Similar to nAMD, PCV can also cause submacular hemorrhage and exudation, resulting in severe impairment of central vision. However, PCV patients do not commonly have drusen, and are usually present as recurrent episodes with less scarring, whereas multiple drusen and progressive scarring are more commonly seen in nAMD patients.4 Regarding disease prevalence, there was no significant difference in the prevalence of nAMD (∼0.46%) between Asian and white populations, although Europeans had a higher prevalence of GA (1.11%) than Asians (0.21%).5 In contrast, the prevalence of PCV is about 3-folds higher in Asians than in whites.6 Regarding treatments, antivascular endothelial growth factor (anti-VEGF) therapy is the mainstay therapeutic approach for nAMD and PCV, but the treatment responses are different. Although nAMD responses well to anti-VEGF monotherapy, PCV usually requires combined anti-VEGF and photodynamic therapy.7 The detailed comparison between nAMD and PCV has been reviewed previously in this journal.4 The similarities and differences in the clinical, epidemiological, and therapeutic profiles suggest that there could be shared and specific components in the mechanisms underlying nAMD and PCV.

Both AMD and PCV are complex diseases resulted from the interaction of multiple genetic and environmental risk factors. Major risk factors include aging, smoking, other inherent systemic diseases such as hypertension, and disease-associated genes and variants.4 This review is to summarize the major nAMD and/or PCV genes and loci that were identified by different genetic strategies, and highlight the ethnic, allelic, and phenotypic diversities.


Early efforts to map the disease loci were usually through linkage analysis, in which a group of microsatellite markers across the genome were mapped on the chromosomal regions that co-segregated with the disease of interest. Such studies were typically conducted in large, multigenerational pedigrees, or alternatively in multiple small nuclear families.8 However, it had been difficult in mapping the disease loci for AMD and PCV because the late disease-onset nature leads to the rarity of large pedigrees. Moreover, the heterogeneities and overlapping in clinical features and the complex genetic architectures also imposed difficulties in the linkage study for AMD and PCV. Nevertheless, there were well-conducted linkage studies reported for AMD, with a number of linkage loci identified, such as 1q25–31, 2q14.3, 2p21, 3p13, 4p16, 4q32, 5q34, 9p13, 9p24, 9q31, 9q33, 10q26, 12q13, 12q23, 15q21, 16p12, 17q25, 18p11, and 20q13.8–11 Among them, the 1q31 and 10q26 loci had later been confirmed to harbor major disease-associated genes. However, each linkage locus may contain a large number of genes; therefore, it has been difficult to pinpoint the causal genes and variants for each of those linkage loci. Moreover, in contrast to AMD, linkage study for PCV has not been reported in the literature. Hence, other genetic strategies should be warranted to identify the susceptibility genes and variants for AMD and PCV.


Regarding the late-onset and multifactorial nature of AMD and PCV, association analysis, which involves the comparison of single or multiple gene variants [usually in a form of single-nucleotide polymorphisms (SNPs)] between unrelated patients and controls, has been proven to be a more appropriate and fruitful strategy for the identification of susceptibility genes. Different approaches of association analysis have been adopted, including candidate gene analysis, genome-wide association study (GWAS), and exome sequencing analysis. Among them, GWAS has been playing an essential role and led to the identification of a large number of gene variants for AMD over the last 15 years.

With the development of the International HapMap Project12 and high-throughput genotyping technology, analyzing simultaneously a large number of SNPs in a defined chromosomal region or across the entire genome became feasible. This has put genome-wide association analysis into practice. For AMD, the first GWAS was reported in 2005, in which a SNP rs1061170 (p.Tyr402His) in the complement factor H (CFH) gene was identified to be strongly associated with AMD in whites.13 The CFH gene is located on chromosome 1q31, a locus previously identified by linkage analyses.9,10 Of note, a small sample of 96 patients and 50 control subjects were included in this GWAS. The successful identification of the CFH gene should attribute to the strong effect of the p.Tyr402His variant and the clearly defined phenotypes for cases and controls, that is, patients with large drusen combined with geographic atrophy or neovascular AMD versus controls with no or only a few small drusen.13 Thus, refined phenotyping is essential in the success of association studies. The second GWAS on AMD was reported in 2006. In this study, 2 SNPs, rs10490924 in PLEKHA1, and rs11200638 in HTRA1, which are in complete linkage disequilibrium (LD) and located in a previous linkage locus 10q26,10,11 were identified to be strongly associated with wet AMD in Chinese.14 In this study, 96 patients with well-defined wet AMD and 130 age-matched healthy control individuals were included, indicating again the importance of refined genotyping.

Since then, GWAS on AMD have been emerging, and to date, 10 GWAS have been reported in different ethnic populations, with SNPs in >40 genes and loci identified: ABCA1, ACAD10, ADAMTS9-AS2, APOE, ARHGAP21, ARMS2-HTRA1, B3GALTL, C2-CFB-SKIV2L, C20orf85, C3, C9, CETP, CFH, CFI, CNN2, COL4A3, COL8A1-FILIP1L, CTRB2-CTRB1, FRK/COL10A1, IER3-DDR1, KMT2E-SRPK2, LIPC, MIR6130-RORB, MMP9, MYRIP, NPLOC4-TSPAN10, PILRB-PILRA, PRLR-SPEF2, RAD51B, RDH5-CD63, REST-C4orf14-POLR2B-IGFBP7, SLC16A8, SYN3-TIMP3, TGFBR1, TIMP3, TMEM97-VTN, TNFRSF10A-LOC389641, TNXB-FKBPL-NOTCH4, TRPM3, and VEGFA.13–22 The identification of these genes and loci suggested the involvement of pathways and regulation of complement activity, lipid metabolism, extracellular matrix remodeling, and angiogenesis.21,22 The odds ratios of the representative SNPs in individual genes/loci were typically falling into the range of 1.1 to 3.0, with a majority <2; thus, each locus only has small to moderate contribution to the risk of the disease. It has been estimated that a group of 52 variants among the 34 loci identified could explain 18%, 27%, and 34% of disease variability, assuming a disease prevalence of 1%, 5%, or 10%, respectively, with the major contribution from variants in CFH, ARMS2-HTRA1, C2-CFB-SKIV2L, and C3.22

Apart from a case–control design to identify genes and loci for advanced AMD, some other GWAS were also conducted to identify genes for early stage,23 bilaterality,24 and progression of AMD.25 A GWAS meta-analysis pinpointed variants in CFH, ARMS2-HTRA1, and ApoE to be associated with early AMD (soft drusen and/or retinal pigment epithelial changes).23 In the GWAS of the bilaterality of AMD, significant associations were identified at STON1-GTF2A1L-LHCGR-FSHR, ARMS2-HTRA1, and LHFP.24 In the GWAS of AMD progression, the ARMS2-HTRA1, CFH, C2-CFB-SKIV2L, C3, LIPC, and CTRB2-CTRB1 loci were found to be associated with AMD progression. Moreover, SNPs at another 3 genes, TNR, ATF7IP2, and MMP9, were associated with the progression to CNV, but not geographic atrophy.25 Of note, the association signal previously detected at MMP9 was specific for wet AMD.22 These findings altogether suggested the phenotypic diversities in AMD genetics, and once again highlighted the importance of refined phenotyping in genetic studies of AMD.


In contrast to AMD, for which a large number of genes were identified by GWAS, currently no gene was identified for PCV by the GWAS approach. Therefore, further large-scale GWAS and/or other genomic analysis should be warranted to identify the genes for PCV. Moreover, GWAS usually identified common SNPs (minor allele frequency > 1%) for diseases and most of the SNPs were located in noncoding regions. This renders difficulty to establish the functional roles of the variants in the diseases. In contrast, disease-associated rare coding variants usually confer a larger effect and are more likely to be functional. In the large-scale GWAS by Fritsche et al, 7 rare variants were identified to be strongly associated with AMD, including 4 in CFH and 1 each in CFI, C9, and C3.22 The minor allele frequency of these rare variants ranged from 0.01% to 1%, and their odds ratios from 1.5 to 47.6.22

GWAS usually provides insufficient coverage for detecting rare variants. Thus, other genomic analytical platforms should be warranted. With the advent of the next-generation sequencing (NGS) platforms, the whole exome and even the entire genome can be sequenced within a reasonable time, enabling the annotation and analysis of most types of variants. In the earlier stage, NGS was mainly adopted to identify the causative genes for diseases that followed Mendelian inheritance in pedigrees, such as Miller syndrome.26 Also, exome sequencing in pedigrees has led to the identification of causative genes at an unprecedented speed for eye diseases, such as retinitis pigmentosa,27 leber congenital amaurosis,28 cone-rod dystrophy,29 congenital stationary night blindness,30 familial exudative vitreoretinopathy,31 hereditary uveal melanoma,32 progressive external ophthalmoplegia,33 anophthalmia and microphthalmia,34 Fuchs corneal dystrophy,35 congenital cataract,36 high myopia,37 and familial primary open angle glaucoma.38

For AMD and PCV, as large disease pedigrees are not common, the NGS has been adopted mainly in detecting rare coding disease-associated variants in unrelated case–control cohorts. By high-throughput sequencing, a rare variant in the CFH gene, p.Arg1210Cys, was identified to be strongly associated with AMD, presenting in 1.4% of cases and <0.1% of controls. This variant was correlated with a 6-year earlier onset of AMD.39 A rare variant, p.Lys155Gln, in the C3 gene was identified in ∼1% of AMD patients and ∼0.4% of controls, conferring a 2.68-fold of increased risk of disease.40 This C3 variant was also identified in other populations with similar effects.41,42 Moreover, in the study of Seddon et al,42 rare variants in the CFI and C9 genes were also associated with AMD. In another study, a rare, highly penetrant variant in CFI, p.Gly119Arg, was found in 0.56% of cases and 0.025% of controls, conferring a 22.2-fold of increased risk of AMD.43 These rare variants have been further confirmed in the large-scale GWAS as mentioned above.22 Exome or high-throughput sequencing has also led the identification of rare, AMD-associated variants in other genes, including COL8A1,44FBN2,45PELI3,46UBE3D,47CFB,48CETP,48,49C6orf223, SLC44A4, and FGD6.49 Among them, FBN2, PELI3, UBE3D, C6orf223, SLC44A4, and FGD6 were not among the genes identified in GWAS. Therefore, these findings altogether suggest that the genetic mechanism of AMD fulfill both the common disease-common variant and common disease-rare variant hypotheses, and apart from detecting rare variants in known genes, NGS is also powerful for identifying new disease-associated genes for AMD.

Of note, exome sequencing has also led to the identification of new genes for PCV. In the study of Huang et al,50 exome sequencing analysis in Chinese cohorts identified a rare p.Lys329Arg variant in the FGD6 gene as significantly associated with PCV [P = 2.19 × 10−16, odds ratio (OR) = 2.12] but not with nAMD (P = 0.26, OR = 1.13). Also, biological analysis suggested that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.50FGD6 is the first gene mapped for PCV directly from PCV patients. Its exact role in the pathogenesis of PCV has yet to be further investigated. Interestingly, in the exome sequencing study by Cheng et al, a rare variant p.Gln257Arg (OR = 0.87) in the FGD6 gene was identified for nAMD.49 Therefore, FGD6 may exert different effects on nAMD and PCV, through different variants. Whether these 2 variants (p.Lys329Arg and p.Gln257Arg) are representing independent haplotypes remains to be elucidated by further detailed sequence analysis between nAMD and PCV. In another exome sequencing study of Wen et al, a rare variant, c.6196A> G, in the IGFN1 gene was significantly associated with PCV (P = 7.1 × 10−11, OR = 9.44), but not with nAMD (P = 0.683, OR = 1.30).51 However, the sample size in this study was small;51 therefore, the role of IGFN1 in PCV remains to be validated in larger cohorts.


Apart from the 2 exome sequencing studies on PCV,50,51 previous efforts to identify the associated genes for PCV mainly relied on the candidate gene approach, and most of the candidate genes were selected from the genes for nAMD.52 Therefore, in the era of genomic study, candidate gene analysis still has a role in the understanding of the genetic profiles of nAMD and PCV.

The candidate genes selection should be guided by the purpose of the study, and they can be the genes previously identified for the disease of interest, genes associated with a similar or related disease, genes in the linkage loci, genes with relevant biological function, and genes in a related pathway. The approaches for candidate gene analysis include selected candidate SNP(s) association analysis, haplotype-tagging SNPs association analysis, and candidate gene(s) sequencing analysis. The methods for data analysis include single SNP association analysis (eg, allelic and genotypic association analysis and meta-analysis) and multiple SNPs analysis (eg, haplotype-based association analysis and gene–gene interaction/joint analysis), with or without adjustment for other factors (eg, age and sex). A candidate gene study usually involved a combination of these components.

Before the advent of GWAS, candidate gene analysis had been playing an essential role in the identification of disease-associated genes for AMD. A typical example is the study of ABCR in AMD. The ABCR gene, which encodes a retinal rod photoreceptor protein, is defective in Stargardt disease, a common hereditary macular dystrophy. Thus, ABCR was considered a candidate gene for AMD, and sequence analysis had linked a group of ABCR variants with AMD.53 However, the association between ABCR and AMD was not significant in other cohorts,54,55 suggesting that ABCR was not a major gene for AMD or could be of population-specific effect. After the identification of CFH associated with AMD by GWAS, analysis candidate genes in the complement pathways had led to the identification of new AMD-associated genes, such as CFHR1-CFHR3,56C2,57CFB,57C3,58 and SERPING1.59 Candidate genes in other pathways have also been implicated in nAMD and PCV, such as those in the angiogenesis pathway (eg, VEGF,60PGF,61 and ANGPT262), fatty acid biosynthesis pathway (eg, ELOVL463), high-density lipoprotein metabolic pathway (eg, CETP64 and ABCG165), and the phagocytic pathway (eg, P2RX4 and P2RX766). Of note, however, not all the candidate genes were widely replicable in other study populations. For example, the SERPING1 gene was initially found to be associated with AMD in the UK samples,59 but later studies and a meta-analysis suggested that SERPING1 was not a major genetic factor for AMD or PCV in East Asians but a risk factor for AMD in whites, suggesting ethnic diversities in the association of SERPING1 with AMD.67

Therefore, the newly identified genes should be replicated in other study cohorts to confirm their roles. In fact, apart from new putative genes identification, reported that candidate gene studies were more commonly about the evaluation of ≥1 AMD-associated genes in specific study cohort(s), serving for specific purposes. First, replication studies are usually conducted to evaluate a newly identified gene variant in separate study cohort(s). For example, after the CFH variant p.Tyr402His was identified, multiple studies have been conducted to evaluate this SNP in AMD among different populations. Although being widely replicated in whites, p.Tyr402His was found not to be a major associated-SNP for AMD in Japanese68 and Chinese,69 likely because of its low frequency in these populations (<5%). Therefore, candidate gene analysis may serve to validate a specific SNP in individual population, and reveal population-specific association patterns.

As such, an extended list of SNPs was usually involved in candidate studies, serving a second purpose of in-depth analysis of individual gene(s). For example, analysis of multiple candidate SNPs in CFH suggested that the common p.Ile62Val variant, rather than p.Tyr402His, was the major coding variant associated with AMD in Chinese.69 By using haplotype analysis of multiple SNPs in CFH, a set of common and rare haplotypes (some were without the p.Tyr402His SNP) were identified to be associated with AMD, suggesting that there were multiple susceptibility alleles in the region and that noncoding CFH variants also play a role in disease susceptibility of AMD.70 When the candidate SNPs were further extended to adjacent genes, haplotype-based association analysis along with conditional analysis would lead to the identification of new associated gene for AMD, such as CFHR1 and CFHR3 near CFH,56 and the causal gene in a locus, such as the SKIV2L SNP rs429608 in the C2-CFB-SKIV2L locus.71 When the scale for gene analysis was extended to whole-gene sequencing, an extended or complete list common and rare variants can be identified for AMD, such as those in the CFH,72CFB,48C3,40CFI,73CETP,48PGF,74ARMS2,75 and HTRA1.76 Finally, when multiple genes were included in candidate gene analysis, interactive and/or joint effects of different genes can be evaluated. For example, a joint effect was identified between CFH rs800292 and HTRA1 rs11200638, with carriers of the homozygous risk genotypes having a 23.3-fold increased risk of nAMD,76 and an interactive effect was found between CFH rs800292 and ANGPT2 rs13269021.62

Third, candidate gene studies can evaluate the effects of common and rare gene variants in different clinical features and subtypes of AMD, including age of disease onset,77 bilaterality,78 severity,79 progression,80 and pharmacogenetics response to antivascular endothelial growth factor therapy.77,81 In particular, candidate gene analyses have led to the identification of multiple associated genes for PCV and enabled the comparison of the genetic profiles between nAMD and PCV. In a meta-analysis, 31 polymorphisms in 10 AMD-associated genes/loci, namely ARMS2, HTRA1, CFH, C2, CFB, RDBP, SKIV2L, CETP, 8p21, and 4q12, were significantly associated with PCV, and 12 polymorphisms at the ARMS2-HTRA1 locus showed significant differences between PCV and nAMD, with the effect sizes being stronger for nAMD.52 In study of Fan et al,82 34 known AMD loci were studied in PCV among East Asians. Significant associations were identified in 8 loci, including ARMS2-HTRA1, CFH, C2-CFB-SKIV2L, CETP, VEGFA, ADAMTS9-AS2, TGFBR1, and COL4A3. PCV and typical AMD were genetically highly correlated (rg = 0.69), with AMD known loci accounting for up to 36% variation of PCV. Moreover, when compared with AMD, weaker association for PCV was observed at ARMS2-HTRA1 and KMT2E-SRPK2.82 Different genetic association patterns between nAMD and PCV were also observed among Chinese, with SKIV2L71 and PGF61 having stronger association with nAMD, while C3 having a male-specific association with PCV.83 These findings suggested that there are shared and distinct genetics components between nAMD and PCV.


To date, a number of genes and variants have been identified for AMD and PCV in different populations, using different genetic approaches. However, current knowledge about the genetic components of PCV remains relatively limited. Moreover, existing evidences suggested that nAMD and PCV have shared and different genetic factors, and the genetic association patterns of certain genes (eg, CFH) were different between East Asians and whites. Therefore, larger-scale genomic studies should be warranted to identify more susceptibility genes for AMD and, in particular, PCV among different populations, and differentiate the genetic architectures between PCV and nAMD. With the advancement of sequencing technology and decreasing price, whole-genome sequencing analysis in large samples has become feasible,84 and it will highly empower the discovery of genomic variants in human diseases. Moreover, the identification of disease genes is only an early step in understanding the molecular mechanisms of AMD and PCV. Further in-depth sequence analysis of the detected associated genes should be warranted to identify the causal variants for those association signals, along with refined genotype–phenotype correlation analysis to unravel the clinical implication of those variants in AMD and PCV. Also, further functional analyses are needed to elucidate the biological roles of those genes and loci in the pathogeneses of AMD and PCV, which in return, may facilitate the identification of new treatment targets and even the development of new therapeutic modalities.


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age-related macular degeneration; genetics; genome-wide association study; next-generation sequencing; polypoidal choroidal vasculopathy

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